Macrobicyclic ligand systems are known in polyether complexing agents and polyamines. However, until the synthesis of macrocyclic compounds incorporating catechol binding subunits, very few other macrobicyclic ligands, particularly those designed to complex Fe (III) or other high-valent transition metals, have been made. Macrocyclic ligands incorporating catechol binding subunits have been made by high-dilution methods, high-dilution being required to favor intramolecular reactions (i.e., cyclization), rather than non-ring forming intermolecular reactions. For example, Kiggen, et al., Ang. Chem. Int. Ed. (Eng.), 23, 714 (1984) disclose synthesis of oligocyclic cavities containing two or three catechol subunits made by high-dilution methods. However, the yields for the macrocyclic compounds using high-dilution methods are typically extremely low, usually about 20% or much less. These methods also suffer from the disadvantage of requiring at least one step under high-dilution conditions requiring a large volume of solvent. This impairs the applicability of the high-dilution process for rapid and commercially feasible processes.
Furthermore, the high-dilution methods usually require multiple step syntheses whereby intermediates are collected and transferred to different vessels for further reaction due to the diversity of conditions required for each step.
It is thus an object of the present invention to provide a novel method for making macrocyclic catecholamides by a template reaction utilizing metal chelates whereby cyclization reactions may be conducted in a single vessel with advantageously high yields of the macrocyclic compound.
These and other objects will be apparent from the following description and appended claims and from practice of the present invention.